Sexually transmitted pathogens such as HIV-1 are highly prevalent and cause extensive mortality and morbidity. In addition, inadequate family planning leads to >50 million unplanned births/year worldwide. Recent surveys indicate that many women would prefer to use a multipurpose prevention method that would protect against acquisition of HIV and other STIs while also providing contraception. Our research program is using an innovative transgenic antibody platform (Nicotiana) to make monoclonal antibodies (mAb-Ns) against HIV-1 and other sexually transmitted pathogens for use in vaginal films and rings to prevent HIV transmission. The purpose of this R21 proposal is to develop and study mAb-Ns against a unique antigen, CD52g, which potentially could block both HIV transmission and unplanned pregnancy. CD52g is produced and secreted by epithelial cells in the male genital tract, and inserts into the plasma membrane of sperm. Anti-CD52g antibodies were described over 40 years ago in a subgroup of infertility patients, and potently agglutinate sperm. We have recently shown that CD52g also inserts into the plasma membranes of other cells in semen, importantly seminal leukocytes which may transmit HIV-1, and we hypothesize that anti-CD52g mAbs may block cell- associated and cell-free HIV transmission. This project has three interrelated specific aims to advance anti-CD52g-N mAbs for use in vaginal products to protect against the sexual transmission of cell-associated and cell-free viruses HIV-1, while at the same time trapping sperm and providing contraception. Our studies are designed to: 1) determine which CD52g antibody isotype is most effective at agglutinating sperm in the genital environment while causing minimum vaginal irritation, 2) confirm that CD52g coats seminal leukocytes and cell- free HIV, and 3) determine whether mAbs directed against CD52g have the potential to prevent cell-free and cell-associated HIV transmission. Results from these studies could pave the way to the use of CD52g mAbs for contraception and HIV prevention.